Dry Granulation Binders, Products, and Use Thereof

ABSTRACT

A method for the preparation of microcrystalline cellulose containing tablets by roller compaction followed by tabletting is disclosed. A tablet formulation is converted to a dry granulate by roller compaction, and the dry granulate lubricated dry granulate and compacted to a tablet. The tablet formulation comprises at least one active, an microcrystalline cellulose containing material, and, optionally other pharmaceutically acceptable excipients. The microcrystalline cellulose containing material has a maximum primary compaction tensile strength of at least 9 MPa or at least 9.5 MPa and a secondary compaction tensile strength of at least 5 MPa, at least 5.5 MPa, or at least 6 MPa. A method for evaluating binders is also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority on U.S. Provisional Application Ser.No. 60/855,106, filed Oct. 27, 2006, on U.S. Provisional ApplicationSer. No. 60/928,166, filed May 8, 2007, and on U.S. ProvisionalApplication Ser. No. 60/855,066, filed Oct. 27, 2006, the disclosures ofwhich are all incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to dry granulation binders with highrecompactability for the manufacture of solid dosage forms by multiplecompaction processes. In particular, this invention relates tomicrocrystalline cellulose based binders where the binder ensures goodgranulate quality, and sufficient recompactability of the granules toobtain tablets of desired tensile strength.

BACKGROUND OF THE INVENTION

Discrete dosages of pharmaceutical compositions suitable for oraladministration are conveniently administered as solid dosage forms,typically tablets. In addition to the therapeutic ingredient oringredients (commonly referred to as “actives,” “active pharmaceuticalingredients,” or “API”), the tablet comprises pharmaceuticallyacceptable materials, known as excipients, that are not actives and donot provide a therapeutic effect, but are added to the tabletformulation to confer specific properties not related to the activity ofthe active.

There are three general methods of preparation of tablets: (1) directcompression; (2) dry granulation; and (3) wet granulation. In directcompression, the powdered material(s) to be included in the tablet(including the active and the excipients) are blended together andcompressed directly without intermediate processing, such asgranulation. Although direct compression is the most effective andfavorable manufacturing process for the production of solid dosageforms, such as tablets, many tablet formulations cannot be processedusing direct compression due.

Granulation procedures may be used where poor flow or low bulk densityof the direct compression mix precludes tabletting by directcompression. Granulation also improves content uniformity of the active,and reduces dust generation. Dry granulation includes mixing theingredients, roller compacting or slugging the mix, dry screening ormilling to a coarse dry granulate, lubricating, and compressing thelubricated granules. The wet granulation procedure includes mixing someor all of the ingredients and thereafter adding solutions of a bindingagent to the mixed powders. The resulting wet mass is screened, dried,lubricated, and compressed into tablets.

In dry granulation, the tablet ingredients are not exposed to moisture,solvents and heat. Thus, it can be used to process moisture, solventand/or heat sensitive actives. Dry granulation can be carried out byslugging or by roller compaction. Slugging is a double compressionprocess. The material to be tabletted is compressed to a largecompressed mass, or “slug,” which is converted to tablets by a secondcompression process. Because slugging is a slow and uneconomic process,roller compaction has become the method of choice for dry granulation.Roller compaction has all the benefits of a granulation process, such asimproved material flow behavior and content uniformity. In addition,roller compaction is high-volume and more economical to operate than wetgranulation.

During the roller compaction process, at least a portion of the tabletformulation (the “granulate formulation”) is compacted and densified bytwo counter-rotating high-pressure rollers, and the resulting materialmilled to uniform size. The resulting granulate may be subsequentlytabletted with or without additional excipients to form tablets. Thetablet is formed by pressure acting on the tablet formulation in a dieon a tablet press. A tablet press includes a lower punch which fits intoa die from the bottom and an upper punch having a corresponding shapeand dimension, which enters the die cavity from the top after the tabletformulation fills the die cavity. The tablet is formed by pressureapplied to the tablet formulation in the die by the lower and upperpunches.

Because of its inherent compactability characteristics, microcrystallinecellulose (MCC) finds widespread use as an excipient in pharmaceuticalformulations. Good binding and disintegration properties are alsoobtained when MCC is used in tablet formulations.

Tablet formation by roller compaction followed by tabletting includestwo compaction steps. However, after the first compaction step, the MCCgranulate may have insufficient compactability for the secondcompaction, i.e., tabletting, step. Therefore a need exists formicrocrystalline containing binders that can be used to prepare soliddosage forms by processes involving multiple compaction steps such asroller compaction and tabletting, or slugging. The binder must havesufficient compactability for the second compaction step.

SUMMARY OF THE INVENTION

The invention is a microcrystalline cellulose containing binder withimproved recompactability, such that it can be used in the manufactureof solid dosage forms by multiple compaction processes. In one aspect,the invention is a composition that comprises at least 60 wt % of amicrocrystalline cellulose containing material and has a primary tensilestrength of at least 9.5 MPa after a primary compaction at 250 MPa andhas a secondary tensile strength of at least 5.5 MPa following secondarycompaction at 250 MPa after a primary compaction at 250 MPa. In anotheraspect, the invention is a binder composition comprising at least 60 wt% of a microcrystalline cellulose containing material, the bindercomposition having primary tensile strength of at least 9.0 MPa after aprimary compaction at 250 MPa and a secondary tensile strength of atleast 5.0 MPa following secondary compaction at 250 MPa after a primarycompaction pressure at 250 MPa, in which the MCC containing material ismicrocrystalline cellulose co-processed with a material selected fromthe group consisting of sugar alcohols and carboxymethyl cellulose.

In another aspect, the invention is a binder composition comprising atleast 60 wt % of a microcrystalline cellulose containing material, thebinder composition having primary tensile strength of at least 9.5 MPaafter a primary compaction at 250 MPa and a maximum secondary tensilestrength of at least 6.0 MPa following secondary compaction after aprimary compaction pressure at 250 MPa. In another aspect, the MCCcontaining material is microcrystalline cellulose co-processed with amaterial selected from the group consisting of sugar alcohols andcarboxymethyl cellulose.

In another aspect, the invention is a binder composition comprising atleast 60 wt % of a microcrystalline cellulose containing material, thebinder composition having a maximum secondary tensile strength of atleast 6.5 MPa following secondary compaction after a primary compactionpressure at 250 MPa, in which the MCC containing material ismicrocrystalline cellulose co-processed with a material selected fromthe group consisting of sugar alcohols and carboxymethyl cellulose.

Granulate formulations, granules, solid dosage forms, and tablets thatcomprise the microcrystalline cellulose containing binders of theinvention are also aspects of the invention. In other aspects, theinvention includes methods for preparing granulate formulations,granules, solid dosage forms, and tablets that comprise themicrocrystalline cellulose containing binder of the invention. Inanother aspect, the invention is a method of testing, evaluating, andselecting binders, especially binders that comprise at least about 40 wt%, or at least about 60% or at least about 65 wt %, of amicrocrystalline cellulose containing material, to determine whichbinders have a high primary compaction and a high secondary compactionand, thus, can be used to prepare solid dosage forms by directcompaction.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the tensile strength of the tablet against primarycompaction pressure for microcrystalline cellulose (AVICEL® PH-105grade) at five different pressures levels.

FIG. 2 is a plot of the tensile strength of the tablet against secondarycompaction pressure for AVICEL® PH-105 microcrystalline celluloseprocessed at different primary compaction pressures.

FIG. 3 is a schematic representation of a roller compaction system thatprovides a continuous process for the granulation of tabletformulations.

FIG. 4 is a plot of the tensile strength of the tablet against secondarycompaction pressure for a co-processed 75:25 mixtures of MCC/mannitolprocessed at different primary compaction pressures.

FIG. 5 is a plot of the tensile strength of the tablet against secondarycompaction pressure for 75:25 dry blends (i.e., non-co-processedphysical mixtures) of MCC/mannitol processed at different primarycompaction pressures.

DETAILED DESCRIPTION OF THE INVENTION

Unless the context indicates otherwise, in the specification and claims,the terms active, excipient, sugar alcohol, and similar terms alsoinclude mixtures of such materials. Unless otherwise specified, allpercentages are percentages by weight and all temperatures are indegrees Centigrade (degrees Celsius). Compression/compressibility refersto the ability of a powder to densify under pressure, while the termscompaction/compactability refer to the ability to yield granules ortablets with specific properties as a result of the compression.Microcrystalline cellulose containing material and MCC containingmaterial refer to materials that are at least about 40 wt %microcrystalline cellulose. Such materials may comprise more than 40 wt% microcrystalline cellulose, for example, at least about 50 wt %microcrystalline cellulose, at least about 60 wt % microcrystallinecellulose, at least about 65 wt % microcrystalline cellulose, at leastabout 70 wt % microcrystalline cellulose, and at least about 75 wt %microcrystalline cellulose.

Dry Granulation

The solid dosage forms comprise the MCC containing material of theinvention, one or more actives, and, optionally, one or more one or morepharmaceutically acceptable excipients and/or lubricants. Solid dosageform manufacture using dry granulation requires two compaction steps.The first occurs during roller compaction or slugging, when thegranulation binder-containing formulation is compacted to form granules.The second occurs during formation of the solid dosage form, ortabletting, when the tablet formulation, which contains the granules, iscompacted into a tablet.

The art teaches that microcrystalline cellulose shows reducedcompactability after repeated compaction events. After the firstcompaction, porosity of the microcrystalline cellulose is reduced and isassociated with reduced compactability of the compacted microcrystallinecellulose relative to the microcrystalline cellulose before the first,or primary, compaction. Thought not being bound by any theory orexplanation, it is thought that a number of hydrogen bonds are formedduring the primary compaction, reducing the number of potential hydrogenbonding sites for the second or subsequent compactions.

However, it has been found that when microcrystalline cellulosecontaining materials undergo primary compaction, the tensile strength ofthe resulting material increases as the compaction pressure increases,but reaches a limiting value, or plateau, at higher compactionpressures. This can be seen in FIG. 1, which shows the tensile strengthof ribbons formed from compaction of AVICEL® PH-105 microcrystallinecellulose at five different primary compaction forces (6.3 kN, 13 kN, 24kN, 33 kN, and 46 kN). These primary compaction forces correspond toprimary compaction pressures of about 50 MPa, about 100 MPa, about 185MPa, about 250 MPa, and about 350 MPa, respectively. A plateau isreached when the primary compaction pressure is about 200 MPa. Uponapplication of higher pressure, the tensile strength does not increasesignificantly, and may even decrease slightly.

FIG. 2 show the tensile strength vs. secondary compaction force for thetablets from dry granulates prepared at the range of primary compactionpressures. The secondary compaction forces of 4 kN, 9 kN, 14 kN, 19 kN,and 27 kN correspond to secondary compaction pressures of about 50 MPa,about 115 MPa, about 180 MPa, about 240 MPa, and about 350 MPa,respectively. The primary compaction pressure for each curve is shown inthe box to the right of each line. The “0 MPa” curve shows material thatwas not recompacted (i.e. direct compression, primary compaction only),which is equivalent to a secondary compaction in which the primarycompaction force was 0 MPa The remaining curves were obtained byrecompaction of materials that were previously compacted at theindicated primary compaction pressure levels. These primary compactionpressures correspond to primary compaction forces shown in FIG. 1. Aprogressive fall off of secondary compactability (“recompactability”)can be seen, which is dependent upon the pressure used for the primarycompaction. Increasing the primary compaction pressure causes“overcompaction”, which causes the secondary compaction tensile strengthto decrease.

For use in tablet formation by roller compaction followed by tabletting,the MCC containing material should have secondary compaction tensilestrength of at least 5.5 MPa, preferably 6.0 MPa, having undergone aprimary compaction of 250 MPa and a secondary compaction of 250 MPa,i.e., the secondary compaction tensile strength is measured on MCCcontaining material that has undergone primary compaction at a pressureapproaching or on the plateau in primary tensile strength.

In one aspect, the composition may have a primary tensile strength of atleast 9.5 MPa after a primary compaction at 250 MPa and a secondarytensile strength of at least 5.5 MPa following a primary compaction at250 MPa and secondary compaction at 250 MPa. In another aspect, thecomposition may have a primary tensile strength of at least 9.5 MPaafter a primary compaction at 250 MPa and a maximum secondary tensilestrength of at least 6.0 MP after a primary compaction pressure at 250MPa and secondary compaction. Maximum tensile strength followingsecondary compaction is typically attained by a secondary compaction ofabout 350 MPa.

When the microcrystalline cellulose has been co-processed with a sugaralcohol or with a carboxymethyl cellulose, the composition may have aprimary tensile strength of at least 9.0 MPa after a primary compactionat 250 MPa and a secondary tensile strength of at least 5.0 MPa after aprimary compaction pressure at 250 MPa and a secondary compaction at 250MPa. In another aspect, when the microcrystalline cellulose has beenco-processed with a sugar alcohol or with carboxymethyl cellulose, thecomposition has a maximum secondary tensile strength of at least 6.5 MPaafter a primary compaction at 250 MPa and secondary compaction.

Several materials have been shown to satisfy this criterion.Co-processed mixtures of sugar alcohols and MCC, such as are describedbelow, satisfy this criterion. Co-processed MCC:mannitol (about 85:15),for example, has a primary compaction tensile strength of 10.0 MPa and asecondary compaction tensile strength maximum of 6.2 MPa. Co-processedMCC:mannitol (about 75:25) has a primary compaction tensile strength of9.5 MPa and a secondary compaction tensile strength maximum of 5.5 MPa.Co-processed MCC:mannitol (about 95:5) has a primary compaction tensilestrength of 10.0 MPa and a secondary compaction tensile strength maximumof 5.5 MPa. Co-processed MCC/carboxymethyl cellulose (CMC) has a primarycompaction tensile strength of 10.0 MPa and a secondary compactiontensile strength maximum of 5.5 MPa.

Although a secondary compaction tensile strength of at least 5.5 MPa issomewhat greater than the tensile strength generally required fortablets, typically about 2 MPa, these values refer to secondary tensilestrengths measured on compact tablets containing only the unformulatedMCC containing material rather than secondary tensile strengths for MCCcontaining materials that have been formulated in tablets. It isanticipated that the tensile strengths of tablets formulated with theseMCC containing materials and other ingredients will be somewhat lower.

Roller Compaction

Roller compaction (also known in the art as “roll compaction”) is a drycompaction/-granulation process of tablet formation, which is used whena tablet formulation does not have the flow characteristics or highenough bulk density necessary for tablet formation. A roller compactoruses pressure to compact and densify the tablet formulation and to bindpowders into granules. Actives that have been processed by rollercompaction include, for example, acetylsalicylic acid (aspirin),acetaminophen, amoxicillin, ibuprofen, penicillin, ranitidine, andstreptomycin.

Granulation is a process of size enlargement in which small particlesare gathered together into larger aggregates in which the originalparticles can still be identified. Uniformly mixed powders (granulateformulations) are compressed between counter rotating rollers to form aribbon of compacted material that is then milled into granules. Aschematic representation of a roller compactor is shown in FIG. 3. Aroller compactor comprises a roller assembly, press frame, hydraulicpressure system, and a feed system. The feed system is locatedimmediately before the rollers and determines the rate of flow of thegranulate formulation to the rollers. The feed system may comprise oneor more feed screws that force the granulate formulation between thecompacting rollers. The granulate formulation is compacted as it passesthrough the two compacting rollers. The volume of the granulateformulation decreases as it passes through the region of maximumpressure, where it is formed into a solid compacted material known as asheet or ribbon. Compaction pressure is provided by the hydraulicpressure system, which can be adjusted to produce the desired compactionpressure. The hydraulic pressure system acts on one of the rollers. Asshown in FIG. 3, the roller compaction process may be a continuousprocess of compacting, milling, screening, and recycling the too largegranules (“Overs”) and too small granules (“Fines”) back to the process.

Various configurations for the rollers are well known in the art and aredescribed, for example, in A. M. Falzone, Ph.D. Thesis, PurdueUniversity, 1990 (U.M.I., Ann Arbor, Mich., Order Number 9313940).Roller compaction equipment is commercially available from theFitzpatrick Company, Elmhurst Ill. USA as CHILSONATOR® roll compactors.This equipment is described in “Introduction to Roll Compaction and theFitzpatrick CHILSONATOR,” published by The Fitzpatrick Company Europe.

Tabletting

Tabletting is well known to those skilled in the art of tabletformation. The tablet is formed by pressure being applied to the tabletformulation on a tablet press. A tablet press includes a lower punchwhich fits into a die from the bottom and an upper punch having acorresponding shape and dimension, which enters the die cavity from thetop after the tablet formulation fills the die cavity. The tablet isformed by pressure applied to the tablet formulation in the die by thelower and upper punches. The ability of the tablet formulation to flowfreely into the die is important in order to ensure that there is auniform filling of the die with continuous flow of tablet formulationfrom hopper to die. Typically, a lubricant, such as magnesium stearate,is added to facilitate ejection of the tablet from the die followingcompaction, and to avoid sticking to the punch faces. Tabletting is welldescribed in pharmaceutics textbooks such as AGENNARO, Remington: TheScience and Practice of Pharmacy, 20th Ed., Lippincott Williams &Wilkins, Baltimore, Md., 2000.

Microcrystalline Cellulose

Microcrystalline cellulose (MCC) is purified, partially depolymerizedcellulose, which may be obtained by hydrolysis of various cellulosesources, such as wood, wood pulps such as bleached sulfate and sulfatepulps, cotton, flax, hemp, bast or leaf fibers, regenerated forms ofcellulose, soy hulls, corn hulls, or nut hulls. It is a white, odorless,tasteless, relatively free flowing powder that is insoluble in water,organic solvents, dilute alkalis and dilute acids.

Hydrolysis may be accomplished by any of several well-known methods.Generally, the source of cellulose, preferably a source ofalpha-cellulose, in the form of a pulp from fibrous plants, is treatedwith a mineral acid, preferably hydrochloric acid. The acid selectivelyattacks the less ordered regions of the cellulose polymer chain, therebyleaving the more crystalline regions, which constitute microcrystallinecellulose. The MCC is then separated from the reaction mixture andwashed to remove by-products. The resulting wet mass, generallycontaining 40-60 wt % moisture, is referred to by several names,including hydrolyzed cellulose, microcrystalline cellulose,microcrystalline cellulose wetcake, or simply wetcake. Preparation ofmicrocrystalline cellulose is disclosed in Battista, U.S. Pats. No.2,978,446 and 3,146,168.

Microcrystalline cellulose is commercially available under the tradename EMCOCEL® from Edward Mendell Co., Inc. and as AVICEL® from FMCCorp. Several grades of microcrystalline cellulose that vary in particlesize, density and moisture content are available, for example, AVICEL®PH-101, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-301, andPH-302.

Co-Processed Composition

The co-processed composition comprises two components, MCC and a sugaralcohol. The two components are present at a weight ratio of about 99:1to 1:99 microcrystalline cellulose:sugar alcohol. When MCC isco-processed with a sugar alcohol, such as mannitol, the weight ratio ofthe two components, MCC:sugar alcohol, is preferably about 70:30 to95:5, more preferably 75:25 to 90:10.

Sugar alcohol refers to polyhydroxy alcohols that include acyclic oralicyclic polyols. Acyclic sugar alcohols have the general formulaC_(n)H_(n+2)(OH)_(n). Typical sugar alcohols include, for example,mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, erythritol,and threitol. Preferred sugar alcohols are those containing four to sixcarbon atoms (i.e, n is 4 to 6), especially five or six carbon atoms (nis 5 or 6).

A particularly preferred sugar alcohol is mannitol [(C₆H₈(OH)₆)][(2R,3R,4R,5R)-hexane-1,2,3,4,5,6-hexol] [CAS #69-65-8]. Mannitol isnon-hydroscopic, produces solutions with relatively low viscosity, andhas a relatively high melting point (about 167-170° C.). Theseproperties allow aqueous microcrystalline cellulose/mannitol slurries tobe readily spray dried to produce co-processed microcrystallinecellulose/mannitol.

The co-processed composition is a particulate composition that has anaverage mean particle size of about 20 microns to about 1000 microns.The mean particle size is typically about 50 microns to about 200microns, more typically about 70 microns to about 120 microns, and evenmore typically 80 microns to 110 microns, for example, about 90 microns.The loose bulk density (LBD) of the co-processed product is typicallyless than or equal to 0.60 g/cm³. The loose bulk density of theco-processed product, with a component ratio of 70:30 to 95:5microcrystalline cellulose:mannitol, for example, is typically about0.35-0.50 g/cm³. The pH is about 3.0 to about 8.5, preferably aboutneutral. When carboxymethyl cellulose is used, the composition maycomprise at least 80 wt % MCC, at least 85 wt % MCC, at least 90 wt %,or at least 95 wt % MCC.

The preparation and properties of co-processed microcrystallinecellulose:sugar alcohol compositions is described in co-filed UnitedStates patent application FMC Docket Number 60560-USA, “Co-ProcessedMicrocrystalline Cellulose and Sugar Alcohol as an Excipient for TabletFormulations,” incorporated herein by reference.

Co-Processing

The process for preparing the co-processed composition involves forminga well-dispersed aqueous slurry of MCC and a sugar alcohol, for examplemannitol. The relative amounts of the two components are adjusted in theslurry to yield the specific weight ratio desired in the final driedco-processed product. Then the aqueous slurry is dried by removing waterfrom it to yield the co-processed product. Preferably, the slurry isdried using spray-drying techniques, which are well known in the art.Other drying techniques, however, such as flash drying, ring drying,tray drying, vacuum drying, radio frequency drying, and microwavedrying, can also be used.

The MCC is preferably wetcake from a conventional MCC manufacturingprocess. Wetcake is MCC that has not yet been dried to yieldconventional MCC as a free-flowing powder. Alternatively, dried MCC maybe re-hydrated to produce an aqueous slurry of MCC. The particle size ofthe MCC used in the aqueous slurry is ordinarily that which isencountered in conventional MCC manufacture.

The aqueous slurry of these two components may be prepared in any ofseveral ways. The sugar alcohol may be introduced into themicrocrystalline cellulose slurry as solid or pre-dissolved in water.Typically the solids concentration is about 5-25 wt % microcrystallinecellulose, preferably about 10-20 wt % microcrystalline cellulose. Theexact amount of sugar alcohol to be added depends on the MCC content ofthe slurry and the ratio of the two components desired in theco-processed product. Water may also be added if a more dilute slurry isrequired. The total solids content of the aqueous slurry is preferablyat least 10 wt %, based on the total slurry weight, and is morepreferably at least 20 wt % solids. The higher solids content levels aredesirable since the amount of water that must be removed during thedrying step is accordingly reduced. The upper limit on solids content inthe aqueous slurry is typically determined by the operating constraintsof the drying apparatus used. With the preferred spray drying procedure,solids contents of 20-30 wt % are representative for aqueous slurriesthat can be readily processed. Ambient or elevated slurry temperatures,of from about 10° C.-80° C. may be used, and higher slurry temperaturesmay be desirable with certain types of drying equipment.

The drying of the well-dispersed aqueous slurry is preferablyaccomplished by spray drying. Conventional spray drying equipment may beused. Operating procedures familiar to those skilled in the spray dryingart are applicable to the spray drying step of this process. Drieroutlet temperature is ordinarily used to control the residual moisturelevel obtained in the co-processed composition. Depending upon theamount and type of drying, the concentration of the MCC and sugaralcohol in the slurry the co-processed product will have differentparticle sizes, densities, pH and moisture content. For this reason thedrying step in the co-processing procedure is especially critical, andfor this reason spray drying is the preferred method for drying.

Spray drying the slurry produces a co-processed composition having aloose bulk density of less than or equal to 0.60 g/cm³, suitably 0.20g/cm³ to 0.60 g/cm³. This produces a composition having a preferredcompactability in the presence of lubricant and a preferredrecompactability compared to either a dry blend of the materials or thecorresponding wet granulate. The loose bulk density may be less than0.55 g/cm³, less than 0.50 g/cm³, less than 0.45 g/cm³, less than 0.40g/cm³, less than 0.35 g/cm³, less than 0.30 g/cm³, and less than 0.25g/cm³. The co-processed product recovered from the drying operation is afree-flowing particulate solid. Particle size of the product is afunction of the spray drier settings, which can be controlled by thoseskilled in the art by adjusting feed rates and atomizer disc speedsduring spray drying.

Solid Dosage Forms

The solid dosage form comprises the MCC containing material of theinvention, one or more actives, and, optionally, one or more one or morepharmaceutically acceptable excipients. Typical tablet formulations areprepared by combining the active or actives with at least one excipientaccording to conventional pharmaceutical compounding techniques. Toprepare a solid dosage form, or tablet, by direct compaction, the tabletformulation must have the necessary physical characteristics. Amongother things, the tablet formulation must be free flowing, must belubricated, and, importantly, must possess sufficient compactability toensure that the solid dosage form remains intact after compaction, andis robust enough for subsequent operations, such as handling, coating,and packaging.

The tablet is formed by pressure being applied to the tablet formulationon a tablet press. A tablet press includes a lower punch that fits intoa die from the bottom and an upper punch having a corresponding shapeand dimension that enters the die cavity from the top after the tabletformulation fills the die cavity. The tablet is formed by pressureapplied on the lower and upper punches. The ability of the tabletformulation to flow freely into the die is important in order to ensurethat there is a uniform filling of the die and a continuous movement ofthe material from the source of the tablet formulation, e.g. a feederhopper. The lubricity of the tablet formulation is crucial in thepreparation of the solid dosage forms because the compressed materialmust be readily released from the punch faces. The tablet must alsoeject cleanly from the die following compression.

Because actives do not always have these properties, methods of tabletformulation have been developed in order to impart these desirablecharacteristics to the tablet formulation. Typically, the tabletformulation comprises one or more additives, or excipients, that impartthe desired free flowing, lubrication, and binding properties to thetablet formulation.

The excipients for dry granulate formulations should have goodrecompactability and dilution potential to allow compaction of thegranules into a tablet. The excipients should not accelerate chemicaland/or physical degradation of the active and should not interfere withits biological availability. The excipients should be physiologicallyinert and should not unintentionally interfere with the tabletdisintegration or dissolution of the active. They should show lowlubricant sensitivity and ensure acceptable active content uniformity.Typical excipients are selected from the group consisting of adisintegrants, glidants, fillers, diluents, colorants, flavorants,stabilizers, and lubricants. The choice of the excipients and thecomposition of the tablet formulation depend on the active, the amountof active in the formulation, the type of tablet, the desiredcharacteristics for both the tablet formulation and the resultingtablet, and the manufacturing process used. These include promptrelease, for which the drug dissolves in a very short time, immediaterelease and modified release, which include most of the orallyadministered tablets that are swallowed.

Pharmaceutically acceptable excipients are well known to those skilledin the art and are disclosed for example, in Staniforth, U.S. Pat. No.6,936,277, and Lee, U.S. Pat. No. 6,936,628. MCC is added to improve thecompactability of the tablets. Excipients such as diluents, binders,glidants, and lubricants are added as processing aids to make thetabletting operation more effective. Still other types of excipientsenhance or retard the rate of disintegration of the tablet, improve thetaste of the tablet, (for example, sweetening agents), or impart a coloror flavor to the tablets.

Lubricants are typically added to prevent the formulation from stickingto the punches during tablet manufacture. Commonly used lubricantsinclude magnesium stearate and calcium stearate. Lubricants typicallycomprise about 0.5 wt % to about 3.0 wt % of the formulation.Antiadherents prevent sticking of the tablet formulation to the punchface and die wall. They are used in combination with magnesium stearatewhen sticking is a problem. Commonly used antiadherents are cornstarchand talc. Diluents, fillers, or bulking agents are frequently added inorder to increase the bulk weight of the material to be tabletted inorder to make the tablet a practical size. This is often necessary wherethe dose of the active is relatively small. Typical fillers includelactose, dicalcium phosphate, calcium carbonate, powdered cellulose,dextrates, mannitol, starch, pre-gelatinized starch, and mixturesthereof. Sugar alcohols, such as, sorbitol, mannitol and xylitol arealso used as fillers, especially in chewable tablet formulations. Themost significant differences between sorbitol and mannitol arehygroscopicity and solubility. Sorbitol is hygroscopic above 65%relative humidity and mannitol is nonhygroscopic. The aqueous solubilityof sorbitol is higher than mannitol.

Binders are added to impart cohesive qualities to the powderedmaterial(s). Commonly used binders include starch, microcrystallinecellulose, and sugars such as sucrose, glucose, dextrose, and lactose.Stabilizers reduce the rate at which the active decomposes. Typicalstabilizers are antioxidants such as ascorbic acid. Disintegrants areoften added to ensure that the tablet has an acceptable dissolution ratein an environment of use (such as the gastrointestinal tract). Thedisintegrant breaks up the tablets and the granules into particles ofactive and excipients. Although MCC and partially pregelatinized starchare frequently used in formulations to perform both the functions ofcompaction and disintegration it is often necessary to addsuper-disintegrants such as croscarmellose sodium, sodium starchglycolate, or crospovidone.

Glidants are used in tablet formulations to improve flow. They are morefrequently used in dry blend, rather than wet granulated formulations.Because of the shape and size of the particles, glidants improve flow inlow concentrations. They are mixed in final tablet formulation in dryform. Most commonly used glidants are alkali metal stearates, colloidalsilicon dioxide (CAB-O-SIL®, SYLOID®, AEROSIL®), and talc.

Desirable characteristics may be imparted to the tablet by colorants(i.e., dyes and pigments), natural or artificial sweeteners, andflavorants. Wetting agents, also called surface active agents orsurfactants, may also be present. The tablet may also be coated.

The size of round tablets is typically about 50 mg to 500 mg and forcapsule-shaped tablets about 200 mg to 1200 mg. However, otherformulations prepared in accordance with the invention may be suitablyshaped for other uses or locations, such as other body cavities, e.g.,periodontal pockets, surgical wounds, and vaginally. For certain uses,such as chewable tablets, antacid tablets, vaginal tablets, andimplants, the tablet may be larger.

The compositions are also suitable use in the NRobe® process to preparesolid dose forms. Solid dose forms for the NRobe® process are preparedby lightly compacting a tablet formulation or granulate formulation toform a powder compact and enrobing the powder compact with a film.Methods and apparatus for forming the enrobed solid dose forms aredisclosed in WO 03/096963, WO 2005/030115, WO 2005/030116, WO2005/030379, and WO 2006/032828, the disclosures of which are allincorporated herein by reference.

INDUSTRIAL APPLICABILITY

The MCC containing materials of the invention are used as binders insolid dosage forms, such as tablets, that comprise one or more actives,and optionally, one or more other excipients. They are particularlyuseful as binders for formulations prepared by direct compression.Although primarily used in pharmaceutical and veterinary applications,they may be used in other areas, such as agriculture, food, cosmetics,and other industrial applications.

The advantageous properties of this invention can be observed byreference to the following examples, which illustrate but do not limitthe invention.

EXAMPLES

Glossary AVICEL ® PH-101 50 Micron microcrystalline cellulose (FMC,Philadelphia, PA USA) AVICEL ® PH-105 20 Micron microcrystallinecellulose (FMC, Philadelphia, PA USA) AVICEL ® PH-200 180 Micronmicrocrystalline cellulose (FMC, Philadelphia, PA USA) AVICEL ® PH-302High density 90 micron microcrystalline cellulose (FMC, Philadelphia, PAUSA) AVICEL ® RC-591 Co-processed colloidal grade MCC:NaCMC (sodiumcarboxymethyl cellulose) (89:11), (FMC, Philadelphia PA) CELLACTOSE ®75:25 α-Lactose monohydrate/25% MCC (Meggle Pharm, Waserburg, Germany)TCP Tricalcium phosphate ETHOCEL ® A4C Methylcellulose (Dow Chemical,Midland MI USA) EMCOMPRESS ® Calcium hydrogen phosphate dihydrate (JRSPharam LP, Patterson, NY USA) GRANULAC ® 200 Lactose monohydrate, 96% ofparticles less than 100 microns (Meggle Pharm, Waserburg, Germany)KOLLIDON ® 90F Polyvinylpyrrolidone (BASF, Ludwigshaften am Rhein,Germany) Lactose monohydrate NF (Foremost Farms, Sparta, WI USA)Magnesium stearate (Mallinckrodt, St. Louis, MO USA) MicroceLac 100Co-processed MCC:Lactose (25:75) (Meggle Pharma, Waserburg, Germany)Parteck 150 Directly compressible sorbitol (Merck KGaA, Darmstadt,Germany) PEARLITOL ® 100 SD Granular mannitol (100 microns) (RoquetteFreres, Lestrem, France) PEARLITOL ® 300 DC Granular mannitol (250microns) (Roquette Freres, Lestrem, France) PEARLITOL ® 400 DC Granularmannitol (360 microns) (Roquette Freres, Lestrem, France) PEARLITOL ®500 DC Granular mannitol (520 microns) (Roquette Freres, Lestrem,France) PROSOLV ® 90 Silicified microcrystalline cellulose (JRS Pharma,Patterson NY USA) StarLac Spray-dried compound consisting of 85%α-lactose monohydrate and 15% maize starch (Meggle Pharm, Waserburg,Germany) Sorbolac 400 α-Lactose monohydrate (Meggle Pharma, Waserburg,Germany) TABLETTOSE ® 100 α-Lactose-monohydrate (Meggle Pharma,Waserburg, Germany) VITACEL ® L600 Powdered cellulose (JRS Pharma,Patterson NY USA) VITACEL ® VE-650 Co-processed MCC:Calcium Carbonate(65:35) (FMC, Philadelphia, PA USA)

General Procedures

The following procedure was used to measure the primary tensile strengthand the secondary tensile strength. Each bulk test material wascompacted at five different compaction pressure levels to produce acompact. Compaction was carried out on a special pneumohydraulic tabletmachine “FlexiTab” as a roller compaction simulator. The compacts areround, flat tablets (13 mm, 750 mg). The crush strength of each compactwas measured, and the tensile strength calculated. The compacts weremilled to granules with a narrow particle size distribution (<1 mm).

To determine recompactability, each of the five resulting granulates wascompacted as five different compaction pressure levels to produce round,flat tablets (10 mm, 500 mg). The crush strength of each tablet wasmeasured and the tensile strength calculated.

Example 1

This example shows that a co-processed MCC/sugar alcohol mixture has ahigher secondary compaction tensile strength maximum than a physicalmixture of the same ingredients in the same proportions.

A co-processed 75:25 mixture of MCC/mannitol was prepared by addingmannitol to MCC wetcake and spray drying the slurry. The co-processed75:25 mixture of MCC/mannitol and a 75:25 non-co-processed, physicalmixture of MCC/mannitol were each evaluated as described in the generalprocedures. The results for the co-processed mixture are shown in FIG.4. The results for the physical mixture are shown in FIG. 5.

The co-processed MCC:mannitol has a maximum primary compaction tensilestrength of 9.5 MPa. The maximum secondary compaction tensile strengthwas 6.5 MPa. In contrast, the physical mixture of MCC and mannitol has amaximum primary compaction tensile strength of 9.0 MPa and a maximumsecondary compaction tensile strength of 5.0 MPa.

Example 2

Co-processed MCC:CMC was prepared at 4% of AQUALON® 7HF grade of sodiumcarboxyl methylcellulose (e.g. 4 g of CMC per 100 g MCC) by thefollowing procedure, which does not subject the MCC to high shearconditions. MCC wetcake was dispersed in deionized water to prepare a15% slurry. The slurry was heated to 60° C., and the slurry pH wasadjusted to 8 using ammonia. Sufficient calcium chloride was added tothe slurry to achieve a concentration of 0.01 moles/liter and thenstirred 5 min using a LIGHTNIN'® mixer. Powdered CMC was added to themixture while stirring with sufficient agitation to disperse the CMC andthen the batch was spray dried under processing conditions to give aparticle size comparable to AVICEL® PH-101

Example 3

A variety of materials were evaluated using the General Procedures. Thetensile strength on primary compaction (primary tensile strength) aftera primary compaction of 250 MPa and the maximum tensile strength onsecondary compaction (secondary tensile strength) for each material aregiven in Table 1 along with the values for the materials prepared and/orevaluated in Examples 1 and 2.

TABLE 1 Tensile Strength (MPa) Material Primary^(a) Secondary^(b)Secondary^(c) Co-processed 10.0 6.2 6.5 MCC:Mannitol (85:15)Co-processed 9.5 5.5 6.5 MCC:Mannitol (75:25) Co-processed 10.0 5.5 6.0MCC:CMC (96:4) Co-processed 10.0 5.5 6.0 MCC:Mannitol (95:5) VITACEL ®VE-650 9.0 6.5 6.5 Methocel A4C 6.0 5.0 5.0 MicroceLac 100 8.0 4.5 5.5AVICEL ® PH-101 + 25% 7.5 4.5 5.0 Methocel A4C (mixture) PROSOLV ® SMCC90 10.0 4.5 4.5 CELLACTOSE ® 6.5 4.0 5.0 AVICEL ® PH-200 9.5 4.0 4.5AVICEL ® PH-101 + 25% 10.0 4.0 4.5 Parteck SI (mixture) AVICEL ®PH-101 + 25% 10.0 4.0 4.0 Kollidon 90F (mixture) Physical mixture of MCC9.5 3.5 5.0 and Mannitol (75:25) AVICEL ® PH-302 8.5 3.5 4.0MCC:Alginate (95:5) 9.0 3.0 4.0 AVICEL ® PH-101 10.0 3.0 3.0 Sorbolac400 3.5 2.5 3.5 Starlac 5.0 2.5 3.5 AVICEL ® RC-591 3.5 2.5 3.0TABLETTOSE ® 100 3.0 2.2 3.0 VITACEL ® L600 7.5 2.2 2.5 (powderedcellulose) AVICEL ® PH-101 + 6.5 2.0 3.0 25% TCP (mixture) GRANULAC ®200 2.5 2.0 3.0 EMCOMPRESS ® 2.0 2.0 3.0 AVICEL ® PH-105 10.5 2.0 2.0^(a)After a 250 MPa primary compaction. ^(b)After a 250 MPa primarycompaction and a 250 MPa secondary compaction. ^(c)Maximum tensilestrength, measured after a 250 MPa primary compaction and a secondarycompaction at about 350 MPa.

Having described the invention, we now claim the following and theirequivalents.

1. A composition, wherein: the composition comprises at least 60 wt % ofa microcrystalline cellulose containing material; the composition has aprimary tensile strength of at least 9.5 MPa after a primary compactionat 250 MPa; and the composition has a secondary tensile strength of atleast 5.5 MPa after a primary compaction at 250 MPa and a secondarycompaction at 250 MPa.
 2. The composition of claim 1 in which: themicrocrystalline cellulose containing material is microcrystallinecellulose co-processed with at least one sugar alcohol, the ratio ofmicrocrystalline cellulose to the at least one sugar alcohol is about70:30 to about 95:5, and the at least one sugar alcohol has at leastfour carbon atoms.
 3. The composition of claim 2 in which the at leastone sugar alcohol is mannitol.
 4. The composition of claim 3 in whichthe composition comprises at least 65 wt % of the microcrystallinecellulose containing material.
 5. A granulate formulation comprising thecomposition of claim 1, at least one active, and at least one lubricant.6. The granulate formulation of claim 5 in which the microcrystallinecellulose containing material is microcrystalline cellulose co-processedwith mannitol. 7.-9. (canceled)
 10. A method comprising the steps of:applying pressure to a granulate formulation to form a compact, andmilling the compact to form a granulate; wherein: the granulateformulation comprises a binder composition, at least one active, atleast one excipient, and at least one lubricant, the binder compositioncomprises at least 60 wt % of a microcrystalline cellulose containingmaterial, and either (1) the binder composition has a maximum primarytensile strength of at least 9.5 MPa after a primary compaction at 250MPa and a secondary tensile strength of at least 5.5 MPa after a primarycompaction at 250 MPa and a secondary compaction at 250 MPa, or (2) themicrocrystalline cellulose containing material is microcrystallinecellulose co-processed with a material selected from the groupconsisting of sugar alcohols and carboxymethyl cellulose, the bindercomposition has a maximum primary tensile strength of at least 9.0 MPaafter a primary compaction at 250 MPa and a secondary tensile strengthof at least 5.0 MPa after a primary compaction at 250 MPa and asecondary compaction after a primary compaction at 250 MPa.
 11. Themethod of claim 10 in which: the microcrystalline cellulose containingmaterial is microcrystalline cellulose co-processed with at least onesugar alcohol, the ratio of microcrystalline cellulose to the at leastone sugar alcohol is about 70:30 to about 95:5, and the at least onesugar alcohol has at least four carbon atoms.
 12. The method of claim 11in which the at least one sugar alcohol is mannitol.
 13. The method ofclaim 10 in which the microcrystalline cellulose containing material ismicrocrystalline cellulose co-processed with carboxymethyl cellulose.14. The method of claim 10 in which the step of applying pressure iscarried out by roller compaction.
 15. The method of claim 10additionally comprising the step of compacting the granules to form asolid dosage form.
 16. A solid dosage form prepared by the method ofclaim
 15. 17. The solid dosage form of claim 16 in which in which themicrocrystalline cellulose containing material is microcrystallinecellulose co-processed with mannitol, and the ratio of microcrystallinecellulose to mannitol is about 70:30 to about 95:5.
 18. The solid dosageform of claim 17 in which the solid dosage form has a tensile strengthof at least 2 MPa.
 19. The solid dosage form of claim 16 in which inwhich the microcrystalline cellulose containing material ismicrocrystalline cellulose co-processed with carboxymethyl cellulose.20. The solid dosage form of claim 19 in which the solid dosage form hasa tensile strength of at least 2 MPa.
 21. A method of evaluatingbinders, in which the binder comprises at least about 40 wt % of amicrocrystalline cellulose containing material; the method comprisingthe steps of: 1) compacting the binder at 250 Pa and measuring theprimary tensile strength; 2) compacting the binder formed in step 1) at250 Pa and measuring the secondary tensile strength; and 3) selectingbinders that in which either (1) the binder has a primary tensilestrength of at least 9.5 MPa and a secondary tensile strength of atleast 6 MPa; or (2) the microcrystalline cellulose containing materialis microcrystalline cellulose co-processed with a material selected fromthe group consisting of sugar alcohols and carboxymethyl cellulose, andthe binder has a maximum primary tensile strength of at least 9.0 MPaand a secondary tensile strength of at least 5.0 MPa.
 22. The method ofclaim 21 in which the binder comprises at least about 60 wt %microcrystalline cellulose